This project studies gene transfer into hematopoietic stem cells for the treatment of disorders of the immune system. specifically, the goal of the project is to develop gene therapy for chronic granulomatous disease (CGD). Patients with CGD have recurrent life-threatening infections because phagocytic cells (neutrophils and monocytes) have a defect in the enzyme that produces microbicidal superoxide and hydrogen peroxide. A clinical trial of a single cycle of gene therapy for the most common autosomal form of CGD (p47phox deficiency) was conducted. Long term followup (18 months) demonstrates the safety of procedures involving transfer of genes to peripheral blood progenitors in culture with intravenous administration of gene corrected progenitors. Corrected autologous progenitors engrafted in the patients providing functionally corrected neutrophils at 1 per 2000 to 30,000 for three to six months. This represents an important first step in demonstrating the feasibility of this approach. In related studies a p47phox-deficient CGD mouse model was used to demonstrate that gene therapy could achieve sufficient corrected neutrophils in peripheral blood (2-10%) to provide improved resistance to infection challenge. In other studies we demonstrated development of a new retrovirus vector construct which could correct the rare p67phox deficient autosomal recessive form of CGD. These clinical, animal and laboratory studies represent important steps toward development of clinically beneficial gene therapy for CGD.